Submissions for variant NM_000169.3(GLA):c.619T>C (p.Tyr207His)

gnomAD frequency: 0.00005  dbSNP: rs372416832

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000418558	SCV000202801	uncertain significance	not provided	2016-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000418558	SCV000535713	likely pathogenic	not provided	2017-01-18	criteria provided, single submitter	clinical testing	The Y207H variant in the GLA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, other missense alterations affecting this residue (Y207S and Y207C) have been reported in association with classic Fabry disease (Shabbeer et al., 2002; Benjamin et al., 2009); in vitro assays demonstrated that the Y207S and Y207C variants significantly diminish alpha-galactosidase-A enzyme activity as compared to the wild-type allele (Wu et al., 2011; Benjamin et al., 2009). Additionally, missense variants in nearby residues (C202YW, W204C, P205T, P205L, P205R, P210S, P210L) have been reported in the Human Gene Mutation Database in association with Fabry disease (Stenson et al., 2014), supporting the functional importance of this region of the protein. The Y207H variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y207H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the information available, the Y207H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae	RCV000798173	SCV000937774	uncertain significance	Fabry disease	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 207 of the GLA protein (p.Tyr207His). This variant is present in population databases (rs372416832, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with GLA-related conditions. ClinVar contains an entry for this variant (Variation ID: 167141). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function with a positive predictive value of 80%. This variant disrupts the p.Tyr207 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19387866, 21598360). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV000798173	SCV001352080	uncertain significance	Fabry disease	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 207 of the GLA protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a newborn with reduced GLA enzyme activity but without a diagnosis of Fabry disease (Kiesling 2014). This variant has been identified in 6/180986 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000798173	SCV001422643	uncertain significance	Fabry disease	2020-01-22	criteria provided, single submitter	curation	The p.Tyr207His variant in GLA has not been previously reported individuals with Fabr disease but has been identified in 0.05% (6/12013) of African chromosomes, including 4 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (ID: 167141) as likely pathogenic by GeneDx and as a VUS by EGL Genetic Diagnostics. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Tyr207His have been reported in association with disease in ClinVar and the literature, and the variant is located in a region of GLA that forms the active site of the enzyme, suggesting that this variant is in a mutational hotspot and functional domain and supports pathogenicity (PMID: 27560961, 19287194; Variation ID: 585078, 197113). In summary, the clinical significance of the p.Tyr207His variant is uncertain. ACMG/AMP Criteria applied: BS1, PM1, PP3, PM5_Supporting (Richards 2015).
Genome-Nilou Lab	RCV000798173	SCV002054811	uncertain significance	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362805	SCV002656952	uncertain significance	Cardiovascular phenotype	2021-07-19	criteria provided, single submitter	clinical testing	The p.Y207H variant (also known as c.619T>C), located in coding exon 4 of the GLA gene, results from a T to C substitution at nucleotide position 619. The tyrosine at codon 207 is replaced by histidine, an amino acid with similar properties. Other alterations affecting the same amino acid, p.Y207C (c.620A>G) and p.Y207S (c.620A>C), have been reported in association with Fabry disease (Shabbeer J et al. Mol. Genet. Metab., 2002 May;76:23-30; Benjamin ER et al. J. Inherit. Metab. Dis., 2009 Jun;32:424-40). Based on data from gnomAD, the C allele has an overall frequency of approximately <0.01% (6/180986), including 4 hemizygotes. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000418558	SCV003816858	uncertain significance	not provided	2023-11-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415998	SCV004107358	uncertain significance	GLA-related disorder	2023-04-26	criteria provided, single submitter	clinical testing	The GLA c.619T>C variant is predicted to result in the amino acid substitution p.Tyr207His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.046% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-100655674-A-G). Other variants at this codon p.Tyr207Ser and p.Tyr207Cys have been reported in individuals with Fabry disease (Shabbeer et al. 2002. PubMed ID: 12175777; Benjamin et al. 2009. PubMed ID: 19387866) and functional studies show significantly reduced a-Galactosidase activity (Wu et al. 2011. PubMed ID: 21598360; Benjamin et al. 2009. PubMed ID: 19387866). However, in contrast to p.Tyr207His, those two alternate variants have not been reported in a large population database (http://gnomad.broadinstitute.org). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV000798173	SCV004821933	uncertain significance	Fabry disease	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with histidine at codon 207 of the GLA protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in a newborn with reduced GLA enzyme activity (Kiesling 2014). This variant has also been identified in 6/180986 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586574	SCV005076619	uncertain significance	not specified	2024-04-24	criteria provided, single submitter	clinical testing	Variant summary: GLA c.619T>C (p.Tyr207His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 180986 control chromosomes, including 4 hemizygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.619T>C in individuals affected with Fabry Disease and no experimental evidence demonstrating its impact on protein function have been reported. Other missense variants at this position have been observed in individuals with Fabry disease (p.Tyr207Ser, p.Tyr207Cys) however this evidence was not sufficient to impact classification of this variant. ClinVar contains an entry for this variant (Variation ID: 167141). Based on the evidence outlined above, the variant was classified as uncertain significance.